Ischaemic diseases, notably myocardial infarction and stroke, are the leading cause of death and disability throughout the world. Following an ischaemic episode, early restoration of blood flow is essential to restrict tissue damage. However, when blood supply is restored to ischaemic cells, the newly returning blood can adversely affect the damaged tissue. This is known as reperfusion injury, and often causes further damage and cell death following an ischaemic episode. It is therefore a therapeutic goal to mitigate and avoid ischaemia/reperfusion (I/R) injury. There are currently no effective therapeutic treatments for ischaemia/reperfusion injury.
Cyclosporin A (CsA) is well known as an immunosuppressive drug. It has been proposed for use in treating ischaemia/reperfusion injury. However, experimental models and pilot trials to investigate the efficacy of cyclosporin in treating ischaemia/reperfusion yielded highly variable and only marginal effects. Further, administration of cyclosporin to patients can lead to adverse side effects, due to the toxicity of the compound. Subsequently, WO 2011/010084 described treatment of ischaemia/reperfusion injury by selective inhibition of mitochondrial cyclophilin D (CyP-D) using cyclosporin conjugated to mitochondrial targeting groups.